U.S. patent application number 11/181255 was filed with the patent office on 2006-05-18 for novel heterocyclyls as selective melanin concentrating hormone receptor antagonists for the treatment of obesity and related disorders.
Invention is credited to Brian A. McKittrick, Li Qiang, Thavalakulamgara K. Sasikumar, Jing Su, Haiqun Tang.
Application Number | 20060106031 11/181255 |
Document ID | / |
Family ID | 35615552 |
Filed Date | 2006-05-18 |
United States Patent
Application |
20060106031 |
Kind Code |
A1 |
Su; Jing ; et al. |
May 18, 2006 |
Novel heterocyclyls as selective melanin concentrating hormone
receptor antagonists for the treatment of obesity and related
disorders
Abstract
The present invention discloses compounds of formula I ##STR1##
wherein m, n, p, R.sup.1, R.sup.2 and X, are herein defined, said
compounds being novel antagonists for melanin-concentrating hormone
(MCH), as well as methods for preparing such compounds. In another
embodiment, the invention discloses pharmaceutical compositions
comprising such MCH antagonists as well as methods of using them to
treat obesity, metabolic disorders, eating disorders such as
hyperphagia, and diabetes.
Inventors: |
Su; Jing; (Scotch Plains,
NJ) ; McKittrick; Brian A.; (New Vernon, NJ) ;
Tang; Haiqun; (Belle Mead, NJ) ; Sasikumar;
Thavalakulamgara K.; (Edison, NJ) ; Qiang; Li;
(Edison, NJ) |
Correspondence
Address: |
SCHERING-PLOUGH CORPORATION;PATENT DEPARTMENT (K-6-1, 1990)
2000 GALLOPING HILL ROAD
KENILWORTH
NJ
07033-0530
US
|
Family ID: |
35615552 |
Appl. No.: |
11/181255 |
Filed: |
July 14, 2005 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
60588492 |
Jul 16, 2004 |
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Current U.S.
Class: |
514/254.02 ;
514/365; 544/369; 548/181; 548/200 |
Current CPC
Class: |
A61P 3/04 20180101; A61P
3/10 20180101; A61P 5/50 20180101; C07D 417/14 20130101; A61P 9/12
20180101; C07D 277/28 20130101; C07D 409/12 20130101; C07D 409/14
20130101; A61P 43/00 20180101; C07D 333/20 20130101; C07D 277/26
20130101; C07D 487/08 20130101; A61P 3/06 20180101; C07D 417/12
20130101 |
Class at
Publication: |
514/254.02 ;
514/365; 544/369; 548/181; 548/200 |
International
Class: |
A61K 31/496 20060101
A61K031/496; A61K 31/427 20060101 A61K031/427; C07D 417/02 20060101
C07D417/02 |
Claims
1. A compound represented by the structural formula ##STR79## or a
pharmaceutically acceptable salt thereof, wherein ##STR80##
represents either (a) a single bond (b) a double bond, or (c) a
cycloalkyl ring where the dashed line is
--(CR.sup.14R.sup.15).sub.s-- where s is 1, 2, 3 or 4; m is 0, 1 or
2; n is 0 or 1, where the sum of n and m is 1 to 3; p is 0, 1, 2, 3
or 4; X is selected from the group consisting of: ##STR81## R.sup.1
is ##STR82## R.sup.2 is ##STR83## where r is 0, 1, 2 or 3; R.sup.3
is --(CR.sup.5R.sup.6).sub.1-3--NR.sup.7R.sup.8, or R.sup.3
##STR84## where t is 1, 2, 3, 4 or 5; R.sup.4 is hydrogen or alkyl;
R.sup.5 and R.sup.6 can be the same or different, each being
hydrogen or alkyl; R.sup.7 is hydrogen, alkyl, acyl,
alkoxycarbonyl, arylsulfonyl or alkylsulfonyl; R.sup.8 is hydrogen,
alkyl, acyl, --C(O)NH.sub.2, --C(O)NH-alkyl, --C(O)N(alkyl).sub.2,
alkoxycarbonyl, arylsulfonyl or alkylsulfonyl; or R.sup.7 and
R.sup.8, taken together and with the nitrogen to which they are
attached, form a heterocyclyl ring, wherein said heterocyclyl ring
can be optionally substituted with 1 or 2 ring system substituents,
each ring system substituent being independently selected from the
group consisting of alkyl, alkenyl, alkynyl, aryl, heteroaryl,
aralkyl, alkylaryl, heteroaralkyl, heteroarylalkenyl,
heteroarylalkynyl, alkylheteroaryl, hydroxy, hydroxyalkyl, alkoxy,
aryloxy, aralkoxy, acyl, aroyl, halo, nitro, cyano, carboxy,
alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, alkylsulfonyl,
arylsulfonyl, heteroarylsulfonyl, alkylthio, arylthio,
heteroarylthio, aralkylthio, heteroaralkylthio, cycloalkyl,
heterocyclyl, --C(.dbd.N--CN)--NH.sub.2, --C(.dbd.NH)--NH.sub.2,
--C(.dbd.NH)--NH(alkyl), Y.sub.1Y.sub.2N--, Y.sub.1Y.sub.2N-alkyl-,
Y.sub.1Y.sub.2NC(O)--, Y.sub.1Y.sub.2NSO.sub.2-- and
--SO.sub.2NY.sub.1Y.sub.2, wherein Y.sub.1 and Y.sub.2 can be the
same or different and are independently selected from the group
consisting of hydrogen, alkyl, aryl, cycloalkyl, and aralkyl;
R.sup.9 is hydrogen or alkyl; R.sup.10 is 1 to 3 moieties, each
R.sup.10 is independently selected from the group consisting of
hydrogen, hydroxy, alkoxy, alkoxyalkyl, hydroxyalkyl, alkyl and
halo, with the proviso that R.sup.10 cannot be halo when it is
attached to the carbon adjacent to N; R.sup.11 is hydrogen, alkyl,
alkoxyalkyl, hydroxyalkyl, acyl, alkoxycarbonyl,
--C(O)NR.sup.7R.sup.8, -alkylC(O)NR.sup.7R.sup.8, arylsulfonyl,
alkylsulfonyl or -alkylC(O).sub.2R.sup.4; R.sup.12 is 1 to 4
moieties, each R.sup.12 is independently selected from the group
consisting of hydrogen, alkyl, alkoxyalkyl or hydroxyalkyl; Ar is
(R.sup.13).sub.u-substituted aryl or (R.sup.13).sub.u-substituted
heteroaryl, where u is a number from 1 to 3; and each R.sup.13 is
independently selected from the group consisting of hydrogen,
hydroxy, halo, alkyl, alkoxy, --OCF.sub.3, --CF.sub.3,
--SO.sub.2-alkyl, --NO.sub.2, --SCF.sub.3 and --CN, or two R.sup.13
moieties on adjacent carbons of the aryl or heteroaryl ring can be
linked to form ##STR85## R.sup.14 is hydrogen, alkyl, --CH.sub.2OH,
halo, --CN, --OH, alkoxy or --NR.sup.7R.sup.8; and R.sup.15 is
hydrogen, alkyl, --CH.sub.2OH, halo, --CN, --OH, alkoxy or
--NR.sup.7R.sup.8.
2. The compound of claim 1 wherein ##STR86## represents either (a)
a double bond or (b) ##STR87##
3. The compound of claim 1 wherein m is 0 or 1, n is 0 or 1 and p
is 2 or 3.
4. The compound of claim 1 wherein X is selected from the group
consisting of: ##STR88##
5. The compound of claim 1 wherein R.sup.1 is ##STR89##
6. The compound of claim 1 wherein R.sup.2 is ##STR90##
7. The compound of claim 1 wherein R.sup.3 is
--CH.sub.2--NR.sup.7R.sup.8, where R.sup.7 and R.sup.8 can be
optionally joined together and with the nitrogen to which they are
attached form a heterocyclyl ring, wherein said heterocyclyl ring
can be optionally substituted with hydroxy.
8. The compound of claim 1 wherein R.sup.7 is hydrogen or alkyl and
R.sup.8 is hydrogen or alkyl.
9. The compound of claim 1 wherein R.sup.10 is 1 or 2 moieties and
each R.sup.10 is independently selected from the group consisting
of hydrogen, hydroxy and alkoxy.
10. The compound of claim 1 wherein R.sup.10 is 1 moiety and
R.sup.10 is independently selected from the group consisting of
hydrogen and hydroxy.
11. The compound of claim 1 wherein R.sup.11 is hydrogen or
alkyl.
12. The compound of claim 1 wherein R.sup.12 is 1 or 2 moieties,
where each R.sup.12 moiety is independently selected from the group
consisting of hydrogen, alkyl, hydroxyalkyl and alkoxyalkyl.
13. The compound of claim 1 wherein Ar is
(R.sup.13).sub.2-substituted aryl, (R.sup.13).sub.2-substituted
heteroaryl, wherein each R.sup.13 is independently selected from
the group consisting of halo and --CF.sub.3.
14. The compound of claim 1 wherein R.sup.14 is hydrogen or alkyl
and R.sup.15 is hydrogen or alkyl.
15. The compound of claim 1 wherein ##STR91## represents either (a)
a double bond or (b) --C(R.sup.14R.sup.15)--; m is 1 or 2; n is 0
or 1; p is 2 or 3; X is selected from the group consisting of
##STR92## R.sup.1 is ##STR93## R.sup.2 is ##STR94## where r is 0,
1, 2 or 3; R.sup.3 is --C(R.sup.5R.sup.6)--NR.sup.7R.sup.8, or
R.sup.7 and R.sup.8 can be optionally joined together and with the
nitrogen to which they are attached, form a heterocyclyl ring,
wherein said heterocyclyl ring can be optionally substituted with
hydroxy; R.sup.7 is hydrogen or alkyl; R.sup.8 is hydrogen or
alkyl; R.sup.10 is 1 or 2 moieties and each R.sup.10 is
independently selected from the group consisting of hydrogen,
hydroxy and alkoxy; R.sup.11 is hydrogen or alkyl; R.sup.12 is
selected from the group consisting of hydrogen, alkyl, hydroxyalkyl
and alkloxyalkyl; Ar is (R.sup.13).sub.2-substituted aryl,
(R.sup.13).sub.2-substituted heteroaryl, wherein each R.sup.13 is
independently selected from the group consisting of halo and
--CF.sub.3; R.sup.14 is hydrogen or alkyl; and R.sup.15 is hydrogen
or alkyl.
16. The compound of claim 1 ##STR95## represents either (a) a
double bond or (b) --C(R.sup.14R.sup.15)--; m is 1; n is 0; p is 2
or 3; X is selected from the group consisting of ##STR96## R.sup.1
is ##STR97## R.sup.2 is ##STR98## R.sup.3 is
--C(R.sup.5R.sup.6)--NR.sup.7R.sup.8 or R.sup.7 and R.sup.8 can be
optionally joined together and with the nitrogen to which they are
attached, form a heterocyclyl ring, wherein said heterocyclyl ring
can be optionally substituted with hydroxy; R.sup.5 and R.sup.6 can
be the same or different, each being hydrogen or alkyl; R.sup.7 is
hydrogen or alkyl; R.sup.8 is hydrogen or alkyl; R.sup.10 is
hydroxy; R.sup.11 is hydrogen or alkyl; R.sup.12 is 1 to 4
moieties, each R.sup.12 is independently selected from the group
consisting of hydrogen and alkyl; Ar is
(R.sup.13).sub.u-substituted phenyl, where u is 2; and each
R.sup.13 is independently selected from the group consisting of
hydrogen, halo, --OCF.sub.3, --CF.sub.3 and --CN; R.sup.14 is
hydrogen or alkyl; and R.sup.15 is hydrogen or alkyl.
17. A compound of formula I selected from the group consisting of
##STR99## ##STR100## ##STR101## ##STR102## ##STR103## ##STR104## or
a pharmaceutically acceptable salt thereof.
18. A compound of formula I selected from the group consisting of
##STR105## ##STR106## or a pharmaceutically acceptable salt
thereof.
19. A method of treating a metabolic disorder, an eating disorder
or diabetes comprising administering to a patient a therapeutically
effective amount of at least one compound of claim 1 to a patient
in need of such treatment.
20. A method of treating a metabolic disorder, an eating disorder
or diabetes comprising administering to a patient a therapeutically
effective amount of at least one compound of claim 17 to a patient
in need of such treatment.
21. A method of treating a metabolic disorder, an eating disorder
or diabetes comprising administering to a patient a therapeutically
effective amount of at least one compound of claim 18 to a patient
in need of such treatment.
22. The method of claim 19 wherein said eating disorder is
hyperphagia.
23. The method of claim 19 wherein said metabolic disorder is
obesity.
24. The method of claim 20 wherein said eating disorder is
hyperphagia.
25. The method of claim 20 wherein said metabolic disorder is
obesity.
26. The method of claim 21 wherein said eating disorder is
hyperphagia.
27. The method of claim 21 wherein said metabolic disorder is
obesity.
28. A method of treating a disorder associated with obesity
comprising administering to a mammal in need of such treatment a
therapeutically effective amount of at least one compound of claim
1, or a pharmaceutically acceptable salt of said compound.
29. A method of treating a disorder associated with obesity
comprising administering to a mammal in need of such treatment a
therapeutically effective amount of at least one compound of claim
17, or a pharmaceutically acceptable salt of said compound.
30. A method of treating a disorder associated with obesity
comprising administering to a mammal in need of such treatment a
therapeutically effective amount of at least one compound of claim
18, or a pharmaceutically acceptable salt of said compound.
31. The method of claim 28 wherein said disorder associated with
obesity is at least one of type II diabetes, insulin resistance,
hyperlipidemia or hypertension.
32. The method of claim 29 wherein said disorder associated with
obesity is at least one of type II diabetes, insulin resistance,
hyperlipidemia or hypertension.
33. The method of claim 30 wherein said disorder associated with
obesity is at least one of type II diabetes, insulin resistance,
hyperlipidemia or hypertension.
34. A method of treating an eating disorder which comprises
administering to a mammal in need of such treatment an amount of a
first compound, said first compound being a compound of claim 1, or
a pharmaceutically acceptable salt of said compound; and a second
compound, said second compound being an antiobesity and/or
anorectic agent selected from the group consisting of a
.beta..sub.3 agonist, a thryomimetic agent, an anorectic agent and
an NPY antagonist; wherein the amounts of the first and second
compounds result in a therapeutic effect.
35. A method of treating an eating disorder which comprises
administering to a mammal in need of such treatment an amount of a
first compound, said first compound being a compound of claim 17,
or a pharmaceutically acceptable salt of said compound; and a
second compound, said second compound being an antiobesity and/or
anorectic agent selected from the group consisting of a
.beta..sub.3 agonist, a thryomimetic agent, an anorectic agent and
an NPY antagonist; wherein the amounts of the first and second
compounds result in a therapeutic effect.
36. A method of treating an eating disorder which comprises
administering to a mammal in need of such treatment an amount of a
first compound, said first compound being a compound of claim 18,
or a pharmaceutically acceptable salt of said compound; and a
second compound, said second compound being an antiobesity and/or
anorectic agent selected from the group consisting of a
.beta..sub.3 agonist, a thryomimetic agent, an anorectic agent and
an NPY antagonist; wherein the amounts of the first and second
compounds result in a therapeutic effect.
37. A pharmaceutical composition which comprises a therapeutically
effective amount of: a first compound, said first compound being a
compound of claim 1, or a pharmaceutically acceptable salt of said
compound; a second compound, said second compound being an
antiobesity and/or anorectic agent selected from the group
consisting of a .beta..sub.3 agonist, a thryomimetic agent, an
anorectic agent and NPY antagonist; and a pharmaceutically
acceptable carrier.
38. A pharmaceutical composition which comprises a therapeutically
effective amount of: a first compound, said first compound being a
compound of claim 17, or a pharmaceutically acceptable salt of said
compound; a second compound, said second compound being an
antiobesity and/or anorectic agent selected from the group
consisting of a .beta..sub.3 agonist, a thryomimetic agent, an
anorectic agent and NPY antagonist; and a pharmaceutically
acceptable carrier.
39. A pharmaceutical composition which comprises a therapeutically
effective amount of: a first compound, said first compound being a
compound of claim 18, or a pharmaceutically acceptable salt of said
compound; a second compound, said second compound being an
antiobesity and/or anorectic agent selected from the group
consisting of a .beta..sub.3 agonist, a thryomimetic agent, an
anorectic agent and NPY antagonist; and a pharmaceutically
acceptable carrier.
40. A pharmaceutical composition which comprises a therapeutically
effective amount of: a first compound, said first compound being a
compound of claim 1, or a pharmaceutically acceptable salt of said
compound; a second compound, said second compound selected from the
group consisting of an aldose reductase inhibitor, a glycogen
phosphorylase inhibitor, a sorbitol dehydrogenase inhibitor, a
protein tyrosine phosphatase 1B inhibitor, a dipeptidyl protease
inhibitor, insulin, an insulin mimetic, metformin, acarbose,
troglitazone, rosaglitazone, pioglitazone, GW-1929, a sulfonylurea,
glipazide, glyburide, and chlorpropamide; and a pharmaceutically
acceptable carrier.
41. A pharmaceutical composition which comprises a therapeutically
effective amount of: a first compound, said first compound being a
compound of claim 17, or a pharmaceutically acceptable salt of said
compound; a second compound, said second compound selected from the
group consisting of an aldose reductase inhibitor, a glycogen
phosphorylase inhibitor, a sorbitol dehydrogenase inhibitor, a
protein tyrosine phosphatase 1B inhibitor, a dipeptidyl protease
inhibitor, insulin, an insulin mimetic, metformin, acarbose,
troglitazone, rosaglitazone, pioglitazone, GW-1929, a sulfonylurea,
glipazide, glyburide, and chlorpropamide; and a pharmaceutically
acceptable carrier.
42. A pharmaceutical composition which comprises a therapeutically
effective amount of: a first compound, said first compound being a
compound of claim 18, or a pharmaceutically acceptable salt of said
compound; a second compound, said second compound being an
antiobesity and/or anorectic agent selected from the group
consisting of a .beta..sub.3 agonist, a thryomimetic agent, an
anorectic agent and NPY antagonist; and a pharmaceutically
acceptable carrier.
43. A pharmaceutical composition comprising a therapeutically
effective amount of at least one compound of claim 1 in combination
with at least one pharmaceutically acceptable carrier.
44. A pharmaceutical composition comprising a therapeutically
effective amount of at least one compound of claim 17 in
combination with at least one pharmaceutically acceptable
carrier.
45. A pharmaceutical composition comprising a therapeutically
effective amount of at least one compound of claim 18 in
combination with at least one pharmaceutically acceptable
carrier.
46. A process for making a pharmaceutical composition comprising
combining at least one compound of claim 1, and at least one
pharmaceutically acceptable carrier.
47. A process for making a pharmaceutical composition comprising
combining at least one compound of claim 17, and at least one
pharmaceutically acceptable carrier.
48. A pharmaceutical composition comprising a therapeutically
effective amount of at least one compound of claim 18 in
combination with at least one pharmaceutically acceptable carrier.
Description
CROSS REFERENCE TO RELATED APPLICATION
[0001] This Application claims the benefit of U.S. Provisional
Application No. 60/588,492 filed Jul. 16, 2004.
FIELD OF THE INVENTION
[0002] This invention relates to antagonists for
melanin-concentrating hormone (MCH) and their use in the treatment
of metabolic and eating disorders, novel compounds having MCH
receptor modulatory activity, pharmaceutical compositions
comprising one or more such modulators, methods of preparing such
modulators and methods of using such modulators to treat obesity,
diabetes and related disorders.
BACKGROUND OF THE INVENTION
[0003] MCH, a cyclic peptide, was first identified over a decade
ago in teleost fish where it appears to regulate color change. More
recently, MCH has been the subject of investigation for its
possible role as a regulator of eating behavior in mammals. As
reported by Shimada et al., Nature, Vol. 396 (17 Dec. 1998), pp.
670-673, MCH-deficient mice have reduced body weight and leanness
due to hypophagia (reduced feeding). In view of their findings, it
was suggested that antagonists of MCH may be effective for the
treatment of obesity. U.S. Pat. No. 5,908,830 discloses a
combination therapy for the treatment of diabetes or obesity
involving the administration of a metabolic rate increasing agent
and a feeding behavior modifying agent, an example of the latter
being an MCH antagonist. Further, MCH receptor antagonists may also
be useful in the treatment of depression and/or anxiety. Borowksy
et al., Nature Medicine, 8, pp. 825-830 (01 Aug. 2002).
[0004] WO 03/047568 discloses compounds having MCH antagonistic
activity. A desired goal is to find compounds that display low hERG
activity to display better and fewer side effects.
SUMMARY OF THE INVENTION
[0005] In one embodiment, this invention provides novel
heterocyclyl compounds having MCH antagonist activity. These
compounds are represented by ##STR2## or a pharmaceutically
acceptable salt or solvate thereof, wherein ##STR3## represents
either (a) a single bond (b) a double bond, or (c) a cycloalkyl
ring where the dashed line is --(CR.sup.14R.sup.15).sub.s-- where s
is 1, 2, 3 or 4; [0006] m is 0, 1 or 2; [0007] n is 0 or 1, where
the sum of n and m is 1 to 3; [0008] p is 0, 1, 2, 3 or 4; [0009] X
is selected from the group consisting of: ##STR4## [0010] R.sup.2
is ##STR5## [0011] where r is 0, 1, 2 or 3; [0012] R.sup.3 is
--(CR.sup.5R.sup.6).sub.1-3--NR.sup.7R.sup.8, or R.sup.3 is
##STR6## [0013] where t is 1, 2, 3, 4 or 5; [0014] R.sup.4 is
hydrogen or alkyl; [0015] R.sup.5 and R.sup.6 can be the same or
different, each being hydrogen or alkyl; [0016] R.sup.7 is
hydrogen, alkyl, acyl, alkoxycarbonyl, arylsulfonyl or
alkylsulfonyl; [0017] R.sup.8 is hydrogen, alkyl, acyl,
--C(O)NH.sub.2, --C(O)NH-alkyl, --C(O)N(alkyl).sub.2,
alkoxycarbonyl, arylsulfonyl or alkylsulfonyl; [0018] or R.sup.7
and R.sup.8, taken together and with the nitrogen to which they are
attached, form a heterocyclyl ring, wherein said heterocyclyl ring
can be optionally substituted with 1 or 2 ring system substituents,
each ring system substituent being independently selected from the
group consisting of alkyl, alkenyl, alkynyl, aryl, heteroaryl,
aralkyl, alkylaryl, heteroaralkyl, heteroarylalkenyl,
heteroarylalkynyl, alkylheteroaryl, hydroxy, hydroxyalkyl, alkoxy,
aryloxy, aralkoxy, acyl, aroyl, halo, nitro, cyano, carboxy,
alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, alkylsulfonyl,
arylsulfonyl, heteroarylsulfonyl, alkylthio, arylthio,
heteroarylthio, aralkylthio, heteroaralkylthio, cycloalkyl,
heterocyclyl, --C(.dbd.N--CN)--NH.sub.2, --C(.dbd.NH)--NH.sub.2,
--C(.dbd.NH)--NH(alkyl), Y.sub.1Y.sub.2N--, Y.sub.1Y.sub.2N-alkyl-,
Y.sub.1Y.sub.2NC(O)--, Y.sub.1Y.sub.2NSO.sub.2-- and
--SO.sub.2NY.sub.1Y.sub.2, wherein Y.sub.1 and Y.sub.2 can be the
same or different and are independently selected from the group
consisting of hydrogen, alkyl, aryl, cycloalkyl, and aralkyl;
[0019] R.sup.9 is hydrogen or alkyl; [0020] R.sup.10 is 1 to 3
moieties, each R.sup.10 is independently selected from the group
consisting of hydrogen, hydroxy, alkoxy, alkoxyalkyl, hydroxyalkyl,
alkyl and halo, with the proviso that R.sup.10 cannot be halo when
it is attached to the carbon adjacent to N; [0021] R.sup.11 is
hydrogen, alkyl, alkoxyalkyl, hydroxyalkyl, acyl, alkoxycarbonyl,
--C(O)NR.sup.7R.sup.8, -alkylC(O)NR.sup.7R.sup.8, arylsulfonyl,
alkylsulfonyl or -alkylC(O).sub.2R.sup.4; [0022] R.sup.12 is 1 to 4
moieties, each R.sup.12 is independently selected from the group
consisting of hydrogen, alkyl, alkoxyalkyl or hydroxyalkyl; [0023]
Ar is (R.sup.13).sub.u-substituted aryl or
(R.sup.13).sub.u-substituted heteroaryl, where u is a number from 1
to 3; and each R.sup.13 is independently selected from the group
consisting of hydrogen, hydroxy, halo, alkyl, alkoxy, --OCF.sub.3,
--CF.sub.3, --SO.sub.2-alkyl, --NO.sub.2, --SCF.sub.3 and --CN, or
two R.sup.13 moieties on adjacent carbons of the aryl or heteroaryl
ring can be linked to form ##STR7## [0024] R.sup.14 is hydrogen,
alkyl, --CH.sub.2OH, halo, --CN, --OH, alkoxy or --NR.sup.7R.sup.8;
and [0025] R.sup.15 is hydrogen, alkyl, --CH.sub.2OH, halo, --CN,
--OH, alkoxy or --NR.sup.7R.sup.8.
[0026] This invention is also directed to pharmaceutical
compositions for the treatment of metabolic disorders such as
obesity, those disorders associated with obesity and eating
disorders such as hyperphagia, using compounds of formula I or
salts or solvates thereof. In one aspect, this invention is
directed to the method of treatment of metabolic disorder(s) such
as obesity, and/or eating disorder(s) such as hyperphagia using the
compound of formula I or salts or solvates thereof. Another
embodiment includes a method of treating an eating disorder which
comprises administering to a mammal in need of such treatment an
amount of a first compound, said first compound being a compound of
formula I or salts or solvates thereof; and a second compound, said
second compound being an antiobesity and/or anorectic agent wherein
the amounts of the first and second compounds result in the desired
therapeutic effect. In another aspect, this invention is directed
to pharmaceutical compositions for the treatment of obesity which
comprise an obesity treating amount of at least one compound of
formula 1, or a pharmaceutically acceptable salt or solvate of said
compound and a pharmaceutically acceptable carrier.
DETAILED DESCRIPTION
[0027] The present invention relates to compounds that are
represented by structural formula I, or a pharmaceutically
acceptable salt or solvate thereof, wherein the various moieties
are as described above.
[0028] One aspect of the invention include those compounds of
formula I wherein ##STR8## represents either (a) a double bond or
(b) ##STR9##
[0029] Another aspect of the invention includes those compounds of
formula I wherein m is 0 or 1, n is 0 or 1 and p is 2 or 3.
[0030] Another aspect of the invention include those compounds of
formula I wherein X is selected from the group consisting of:
##STR10##
[0031] Another aspect of the invention include those compounds of
formula I wherein R.sup.1 is ##STR11##
[0032] Another aspect of the invention are compounds of formula I
wherein R.sup.2 is ##STR12##
[0033] Another aspect of the invention are compounds of formula I
wherein R.sup.3 is --CH.sub.2--NR.sup.7R.sup.8, where R.sup.7 and
R.sup.8 can be optionally joined together and with the nitrogen to
which they are attached form a heterocyclyl ring, wherein said
heterocyclyl ring can be optionally substituted with hydroxy.
[0034] Another aspect of the invention are compounds of formula I
wherein R.sup.7 is hydrogen or alkyl and R.sup.8 is hydrogen or
alkyl.
[0035] Another aspect of the invention are compounds of formula I
wherein R.sup.10 is 1 or 2 moieties and each R.sup.10 is
independently selected from the group consisting of hydrogen,
hydroxy and alkoxy.
[0036] Another aspect of the invention are compounds of formula I
wherein R.sup.10 is 1 moiety and each R.sup.10 is independently
selected from the group consisting of hydrogen and hydroxy.
[0037] Another aspect of the invention are compounds of formula I
wherein R.sup.11 is hydrogen or alkyl.
[0038] Another aspect of the invention are compounds of formula I
wherein R.sup.12 is 1 or 2 moieties, where each R.sup.12 moiety is
independently selected from the group consisting of hydrogen,
alkyl, hydroxyalkyl and alkoxyalkyl.
[0039] Another aspect of the invention are compounds of formula I
wherein Ar is (R.sup.13).sub.2-substituted aryl,
(R.sup.13).sub.2-substituted heteroaryl, wherein each R.sup.13 is
independently selected from the group consisting of halo and
--CF.sub.3.
[0040] Another aspect of the invention are compounds of formula I
wherein R.sup.14 is hydrogen or alkyl and R.sup.15 is hydrogen or
alkyl.
[0041] Additional aspects of the invention include those compounds
of formula I wherein ##STR13## represents either (a) a double bond
or (b) --C(R.sup.14R.sup.15)--; [0042] m is 1 or 2; [0043] n is 0
or 1; [0044] p is 2 or 3; [0045] X is selected from the group
consisting of ##STR14## [0046] R.sup.1 is ##STR15## [0047] R.sup.2
is ##STR16## [0048] where r is 0, 1, 2 or 3; [0049] R.sup.3 is
--C(R.sup.5R.sup.6)--NR.sup.7R.sup.8, or R.sup.7 and R.sup.8 can be
optionally joined together and with the nitrogen to which they are
attached, form a heterocyclyl ring, wherein said heterocyclyl ring
can be optionally substituted with hydroxy; [0050] R.sup.7 is
hydrogen or alkyl; [0051] R.sup.8 is hydrogen or alkyl; [0052]
R.sup.10 is 1 or 2 moieties and each R.sup.10 is independently
selected from the group consisting of hydrogen, hydroxy and alkoxy;
[0053] R.sup.11 is hydrogen or alkyl; [0054] R.sup.12 is selected
from the group consisting of hydrogen, alkyl, hydroxyalkyl and
alkloxyalkyl; [0055] Ar is (R.sup.13).sub.2-substituted aryl,
(R.sup.13).sub.2-substituted heteroaryl, wherein each R.sup.13 is
independently selected from the group consisting of halo and
--CF.sub.3; [0056] R.sup.14 is hydrogen or alkyl; and [0057]
R.sup.15 is hydrogen or alkyl.
[0058] Additional aspects of the invention include those compounds
of formula I wherein ##STR17## represents either (a) a double bond
or (b) --C(R.sup.14R.sup.15)--; [0059] m is 1; [0060] n is 0;
[0061] p is 2 or 3; [0062] X is selected from the group consisting
of ##STR18## [0063] R.sup.1 is ##STR19## [0064] R.sup.2 is
##STR20## [0065] R.sup.3 is --C(R.sup.5R.sup.6)--NR.sup.7R.sup.8,
or R.sup.7 and R.sup.8 can be optionally joined together and with
the nitrogen to which they are attached, form a heterocyclyl ring,
wherein said heterocyclyl ring can be optionally substituted with
hydroxy; [0066] R.sup.5 and R.sup.6 can be the same or different,
each being hydrogen or alkyl; [0067] R.sup.7 is hydrogen or alkyl;
[0068] R.sup.8 is hydrogen or alkyl; [0069] R.sup.10 is hydroxy;
[0070] R.sup.11 is hydrogen or alkyl; [0071] R.sup.12 is 1 to 4
moieties, each R.sup.12 is independently selected from the group
consisting of hydrogen and alkyl; [0072] Ar is
(R.sup.13).sub.u-substituted phenyl, where u is 2; and each
R.sup.13 is independently selected from the group consisting of
hydrogen, halo, --OCF.sub.3, --CF.sub.3 and --CN; [0073] R.sup.14
is hydrogen or alkyl; and [0074] R.sup.15 is hydrogen or alkyl.
[0075] Preferred embodiments of formula I include compounds
selected from the group consisting of Examples 1-21.
[0076] Additional preferred embodiments of formula I include
compounds of the following formulae: ##STR21## ##STR22##
[0077] Except where stated otherwise, the following definitions
apply throughout the present specification and claims. These
definitions apply regardless of whether a term is used by itself or
in combination with other terms. Hence the definition of "alkyl"
applies to "alkyl" as well as to the "alkyl" portions of "alkoxy",
"cycloalkyl" and so forth.
[0078] As used above, and throughout the specification, the
following terms, unless otherwise indicated, shall be understood to
have the following meanings:
[0079] "Patient" includes both human and animals.
[0080] "Mammal" means humans and other mammalian animals.
[0081] "Alkyl" means an aliphatic hydrocarbon group which may be
straight or branched and comprising about 1 to about 20 carbon
atoms in the chain. Preferred alkyl groups contain about 1 to about
12 carbon atoms in the chain. More preferred alkyl groups contain
about 1 to about 6 carbon atoms in the chain. Branched means that
one or more lower alkyl groups such as methyl, ethyl or propyl, are
attached to a linear alkyl chain. "Lower alkyl" means a group
having about 1 to about 6 carbon atoms in the chain which may be
straight or branched. The term "substituted alkyl" means that the
alkyl group may be substituted by one or more substituents which
may be the same or different, each substituent being independently
selected from the group consisting of halo, alkyl, aryl,
cycloalkyl, cyano, hydroxy, alkoxy, alkylthio, amino, --NH(alkyl),
--NH(cycloalkyl), --N(alkyl).sub.2, carboxy and --C(O)O-alkyl.
Non-limiting examples of suitable alkyl groups include methyl,
ethyl, n-propyl, isopropyl and t-butyl.
[0082] "Alkenyl" means an aliphatic hydrocarbon group containing at
least one carbon-carbon double bond and which may be straight or
branched and comprising about 2 to about 15 carbon atoms in the
chain. Preferred alkenyl groups have about 2 to about 12 carbon
atoms in the chain; and more preferably about 2 to about 6 carbon
atoms in the chain. Branched means that one or more lower alkyl
groups such as methyl, ethyl or propyl, are attached to a linear
alkenyl chain. "Lower alkenyl" means about 2 to about 6 carbon
atoms in the chain which may be straight or branched. The term
"substituted alkenyl" means that the alkenyl group may be
substituted by one or more substituents which may be the same or
different, each substituent being independently selected from the
group consisting of halo, alkyl. aryl, cycloalkyl, cyano, alkoxy
and --S(alkyl). Non-limiting examples of suitable alkenyl groups
include ethenyl, propenyl, n-butenyl, 3-methylbut-2-enyl,
n-pentenyl, octenyl and decenyl.
[0083] "Alkynyl" means an aliphatic hydrocarbon group containing at
least one carbon-carbon triple bond and which may be straight or
branched and comprising about 2 to about 15 carbon atoms in the
chain. Preferred alkynyl groups have about 2 to about 12 carbon
atoms in the chain; and more preferably about 2 to about 4 carbon
atoms in the chain. Branched means that one or more lower alkyl
groups such as methyl, ethyl or propyl, are attached to a linear
alkynyl chain. "Lower alkynyl" means about 2 to about 6 carbon
atoms in the chain which may be straight or branched. Non-limiting
examples of suitable alkynyl groups include ethynyl, propynyl,
2-butynyl and 3-methylbutynyl. The term "substituted alkynyl" means
that the alkynyl group may be substituted by one or more
substituents which may be the same or different, each substituent
being independently selected from the group consisting of alkyl,
aryl and cycloalkyl.
[0084] "Aryl" means an aromatic monocyclic or multicyclic ring
system comprising about 6 to about 14 carbon atoms, preferably
about 6 to about 10 carbon atoms. The aryl group can be optionally
substituted with one or more "ring system substituents" which may
be the same or different, and are as defined herein. Non-limiting
examples of suitable aryl groups include phenyl and naphthyl.
[0085] "Heteroaryl" means an aromatic monocyclic or multicyclic
ring system comprising about 5 to about 14 ring atoms, preferably
about 5 to about 10 ring atoms, in which one or more of the ring
atoms is an element other than carbon, for example nitrogen, oxygen
or sulfur, alone or in combination. Preferred heteroaryls contain
about 5 to about 6 ring atoms. The "heteroaryl" can be optionally
substituted by one or more "ring system substituents" which may be
the same or different, and are as defined herein. The prefix aza,
oxa or thia before the heteroaryl root name means that at least a
nitrogen, oxygen or sulfur atom respectively, is present as a ring
atom. A nitrogen atom of a heteroaryl can be optionally oxidized to
the corresponding N-oxide. Non-limiting examples of suitable
heteroaryls include pyridyl, pyrazinyl, furanyl, thienyl,
pyrimidinyl, pyridone (including N-substituted pyridones),
isoxazolyl, isothiazolyl, oxazolyl, thiazolyl, pyrazolyl,
furazanyl, pyrrolyl, pyrazolyl, triazolyl, 1,2,4-thiadiazolyl,
pyrazinyl, pyridazinyl, quinoxalinyl, phthalazinyl, oxindolyl,
imidazo[1,2-a]pyridinyl, imidazo[2,1-b]thiazolyl, benzofurazanyl,
indolyl, azaindolyl, benzimidazolyl, benzothienyl, quinolinyl,
imidazolyl, thienopyridyl, quinazolinyl, thienopyrimidyl,
pyrrolopyridyl, imidazopyridyl, isoquinolinyl, benzoazaindolyl,
1,2,4-triazinyl, benzothiazolyl and the like. The term "heteroaryl"
also refers to partially saturated heteroaryl moieties such as, for
example, tetrahydroisoquinolyl, tetrahydroquinolyl and the
like.
[0086] "Aralkyl" or "arylalkyl" means an aryl-alkyl- group in which
the aryl and alkyl are as previously described. Preferred aralkyls
comprise a lower alkyl group. Non-limiting examples of suitable
aralkyl groups include benzyl, 2-phenethyl and naphthalenylmethyl.
The bond to the parent moiety is through the alkyl.
[0087] "Alkylaryl" means an alkyl-aryl- group in which the alkyl
and aryl are as previously described. Preferred alkylaryls comprise
a lower alkyl group. Non-limiting example of a suitable alkylaryl
group is tolyl. The bond to the parent moiety is through the
aryl.
[0088] "Cycloalkyl" means a non-aromatic mono- or multicyclic ring
system comprising about 3 to about 10 carbon atoms, preferably
about 5 to about 10 carbon atoms. Preferred cycloalkyl rings
contain about 5 to about 7 ring atoms. The cycloalkyl can be
optionally substituted with one or more "ring system substituents"
which may be the same or different, and are as defined above.
Non-limiting examples of suitable monocyclic cycloalkyls include
cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl and the like.
Non-limiting examples of suitable multicyclic cycloalkyls include
1-decalinyl, norbornyl, adamantyl and the like, as well as
partially saturated species such as, for example, indanyl,
tetrahydronaphthyl and the like.
[0089] "Halogen" means fluorine, chlorine, bromine, or iodine.
Preferred are fluorine, chlorine and bromine.
[0090] "Halo" means fluoro, chloro, bromo or iodo. Preferred are
fluoro, chloro and bromo.
[0091] "Ring system substituent" means a substituent attached to an
aromatic or non-aromatic ring system which, for example, replaces
an available hydrogen on the ring system. Ring system substituents
may be the same or different, each being independently selected
from the group consisting of alkyl, alkenyl, alkynyl, aryl,
heteroaryl, aralkyl, alkylaryl, heteroaralkyl, heteroarylalkenyl,
heteroarylalkynyl, alkylheteroaryl, hydroxy, hydroxyalkyl, alkoxy,
aryloxy, aralkoxy, acyl, aroyl, halo, nitro, cyano, carboxy,
alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, alkylsulfonyl,
arylsulfonyl, heteroarylsulfonyl, alkylthio, arylthio,
heteroarylthio, aralkylthio, heteroaralkylthio, cycloalkyl,
heterocyclyl, --C(.dbd.N--CN)--NH.sub.2, --C(.dbd.NH)--NH.sub.2,
--C(.dbd.NH)--NH(alkyl), Y.sub.1Y.sub.2N--, Y.sub.1Y.sub.2N-alkyl-,
Y.sub.1Y.sub.2NC(O)--, Y.sub.1Y.sub.2NSO.sub.2-- and
--SO.sub.2NY.sub.1Y.sub.2, wherein Y.sub.1 and Y.sub.2 can be the
same or different and are independently selected from the group
consisting of hydrogen, alkyl, aryl, cycloalkyl, and aralkyl. "Ring
system substituent" may also mean a single moiety which
simultaneously replaces two available hydrogens on two adjacent
carbon atoms (one H on each carbon) on a ring system. Examples of
such moiety are methylene dioxy, ethylenedioxy,
--C(CH.sub.3).sub.2-- and the like which form moieties such as, for
example: ##STR23##
[0092] "Heterocyclyl" means a non-aromatic saturated monocyclic or
multicyclic ring system comprising about 3 to about 10 ring atoms,
preferably about 4 to about 7 ring atoms, in which one or more of
the atoms in the ring system is an element other than carbon, for
example nitrogen, oxygen or sulfur, alone or in combination. There
are no adjacent oxygen and/or sulfur atoms present in the ring
system. Preferred heterocyclyls contain about 5 to about 6 ring
atoms. The prefix aza, oxa or thia before the heterocyclyl root
name means that at least a nitrogen, oxygen or sulfur atom
respectively is present as a ring atom. Any --NH in a heterocyclyl
ring may exist protected such as, for example, as an --N(Boc),
--N(CBz), --N(Tos) group and the like; such protections are also
considered part of this invention. The heterocyclyl can be
optionally substituted by one or more "ring system substituents"
which may be the same or different, and are as defined herein. The
nitrogen or sulfur atom of the heterocyclyl can be optionally
oxidized to the corresponding N-oxide, S-oxide or S,S-dioxide.
Non-limiting examples of suitable monocyclic heterocyclyl rings
include piperidyl, pyrrolidinyl, piperazinyl, morpholinyl,
thiomorpholinyl, thiazolidinyl, 1,4-dioxanyl, tetrahydrofuranyl,
tetrahydrothiophenyl, lactam, lactone, and the like.
[0093] It should be noted that in hetero-atom containing ring
systems of this invention, there are no hydroxyl groups on carbon
atoms adjacent to a N, O or S, as well as there are no N or S
groups on carbon adjacent to another heteroatom. Thus, for example,
in the ring: ##STR24## there is no --OH attached directly to
carbons marked 2 and 5.
[0094] It should also be noted that tautomeric forms such as, for
example, the moieties: ##STR25## are considered equivalent in
certain embodiments of this invention.
[0095] "Alkynylalkyl" means an alkynyl-alkyl- group in which the
alkynyl and alkyl are as previously described. Preferred
alkynylalkyls contain a lower alkynyl and a lower alkyl group. The
bond to the parent moiety is through the alkyl. Non-limiting
examples of suitable alkynylalkyl groups include
propargylmethyl.
[0096] "Heteroaralkyl" means a heteroaryl-alkyl- group in which the
heteroaryl and alkyl are as previously described. Preferred
heteroaralkyls contain a lower alkyl group. Non-limiting examples
of suitable aralkyl groups include pyridylmethyl, and
quinolin-3-ylmethyl. The bond to the parent moiety is through the
alkyl.
[0097] "Heteroaralkylthio" means a heteroaralkyl-S-- group in which
the heteroaralkyl is as previously described. Preferred
heteroaralkylthios contain a lower alkyl group. The bond to the
parent moiety is through the sulfur.
[0098] "Heteroarylalkenyl" means a heteroaryl-alkenyl group in
which the heteroaryl and the alkenyl are as previously described.
Preferred heteroarylalkenyls contain a lower alkenyl group. The
bond to the parent moiety is through the alkyl.
[0099] "Heteroarylalkynyl" means a heteroaryl-alkynyl group in
which the heteroaryl and the alkynyl are as previously described.
Preferred heteroarylalkynyls contain a lower alkynyl group. The
bond to the parent moiety is through the alkynyl.
[0100] "Hydroxyalkyl" means a HO-alkyl- group in which alkyl is as
previously defined. Preferred hydroxyalkyls contain lower alkyl.
Non-limiting examples of suitable hydroxyalkyl groups include
hydroxymethyl and 2-hydroxyethyl.
[0101] "Acyl" means an H--C(O)--, alkyl-C(O)-- or
cycloalkyl-C(O)--, group in which the various groups are as
previously described. The bond to the parent moiety is through the
carbonyl. Preferred acyls contain a lower alkyl. Non-limiting
examples of suitable acyl groups include formyl, acetyl and
propanoyl.
[0102] "Aroyl" means an aryl-C(O)-- group in which the aryl group
is as previously described. The bond to the parent moiety is
through the carbonyl. Non-limiting examples of suitable groups
include benzoyl and 1-naphthoyl.
[0103] "Alkoxy" means an alkyl-O-- group in which the alkyl group
is as previously described. Non-limiting examples of suitable
alkoxy groups include methoxy, ethoxy, n-propoxy, isopropoxy and
n-butoxy. The bond to the parent moiety is through the ether
oxygen.
[0104] "Alkoxyalkyl" means an alkoxy-alkyl group in which the
alkoxy and alkyl groups are as previously described. Non-limiting
examples of suitable alkoxyalkyl groups include methoxymethyl and
ethoxymethyl. The bond to the parent moiety is through the alkyl
group.
[0105] "Aryloxy" means an aryl-O-- group in which the aryl group is
as previously described. Non-limiting examples of suitable aryloxy
groups include phenoxy and naphthoxy. The bond to the parent moiety
is through the ether oxygen.
[0106] "Aralkyloxy" means an aralkyl-O-- group in which the aralkyl
group is as previously described. Non-limiting examples of suitable
aralkyloxy groups include benzyloxy and 1- or 2-naphthalenemethoxy.
The bond to the parent moiety is through the ether oxygen.
[0107] "Alkylheteroaryl" means an alkyl-heteroaryl group in which
the alkyl and heteroaryl groups are as previously described. The
bond to the parent moiety is through the heteroaryl.
[0108] "Alkylthio" means an alkyl-S-- group in which the alkyl
group is as previously described. Non-limiting examples of suitable
alkylthio groups include methylthio and ethylthio. The bond to the
parent moiety is through the sulfur.
[0109] "Arylthio" means an aryl-S-- group in which the aryl group
is as previously described. Non-limiting examples of suitable
arylthio groups include phenylthio and naphthylthio. The bond to
the parent moiety is through the sulfur.
[0110] "Aralkylthio" means an aralkyl-S-- group in which the
aralkyl group is as previously described. Non-limiting example of a
suitable aralkylthio group is benzylthio. The bond to the parent
moiety is through the sulfur.
[0111] "Alkoxycarbonyl" means an alkyl-O--C(O)-- group in which the
alkyl group is as previously described. Non-limiting examples of
suitable alkoxycarbonyl groups include methoxycarbonyl and
ethoxycarbonyl. The bond to the parent moiety is through the
carbonyl.
[0112] "Aryloxycarbonyl" means an aryl-O--C(O)-- group in which the
aryl group is as previously described. Non-limiting examples of
suitable aryloxycarbonyl groups include phenoxycarbonyl and
naphthoxycarbonyl. The bond to the parent moiety is through the
carbonyl.
[0113] "Aralkoxy" means an aralkyl-O-- group in which the aralkyl
group is as previously described. A non-limiting example of a
suitable aralkoxy is benzyloxy. The bond to the parent moiety is
through the oxygen.
[0114] "Aralkoxycarbonyl" means an aralkyl-O--C(O)-- group in which
the aralkyl group is as previously described. Non-limiting example
of a suitable aralkoxycarbonyl group is benzyloxycarbonyl. The bond
to the parent moiety is through the carbonyl.
[0115] "Alkylsulfonyl" means an alkyl-S(O.sub.2)-- group in which
the alkyl group is as previously described. Preferred groups are
those in which the alkyl group is lower alkyl. The bond to the
parent moiety is through the sulfonyl.
[0116] "Arylsulfonyl" means an aryl-S(O.sub.2)-- group in which the
aryl group is as previously described. The bond to the parent
moiety is through the sulfonyl.
[0117] "Heteroarylsulfonyl" means a heteroaryl-S(O.sub.2)-- group
in which the heteroaryl group is as previously described. The bond
to the parent moiety is through the sulfonyl.
[0118] "Heteroarylthio" means a heteroaryl-S-- group in which the
heteroaryl group is as previously described. The bond to the parent
moiety is through the sulfur.
[0119] The term "substituted" means that one or more hydrogens on
the designated atom is replaced with a selection from the indicated
group, provided that the designated atom's normal valency under the
existing circumstances is not exceeded, and that the substitution
results in a stable compound. Combinations of substituents and/or
variables are permissible only if such combinations result in
stable compounds. By "stable compound` or "stable structure" is
meant a compound that is sufficiently robust to survive isolation
to a useful degree of purity from a reaction mixture, and
formulation into an efficacious therapeutic agent.
[0120] The term "optionally substituted" means optional
substitution with the specified groups, radicals or moieties.
[0121] The term "isolated" or "in isolated form" for a compound
refers to the physical state of said compound after being isolated
from a synthetic process or natural source or combination thereof.
The term "purified" or "in purified form" for a compound refers to
the physical state of said compound after being obtained from a
purification process or processes described herein or well known to
the skilled artisan, in sufficient purity to be characterizable by
standard analytical techniques described herein or well known to
the skilled artisan.
[0122] It should also be noted that any heteroatom with unsatisfied
valences in the text, schemes, examples and Tables herein is
assumed to have the hydrogen atom(s) to satisfy the valences.
[0123] When a functional group in a compound is termed "protected",
this means that the group is in modified form to preclude undesired
side reactions at the protected site when the compound is subjected
to a reaction. Suitable protecting groups will be recognized by
those with ordinary skill in the art as well as by reference to
standard textbooks such as, for example, T. W. Greene et al,
Protective Groups in organic Synthesis (1991), Wiley, New York.
[0124] When any variable (e.g., aryl, heterocycle, R.sup.2, etc.)
occurs more than one time in any constituent or in Formula I, its
definition on each occurrence is independent of its definition at
every other occurrence.
[0125] As used herein, the term "composition" is intended to
encompass a product comprising the specified ingredients in the
specified amounts, as well as any product which results, directly
or indirectly, from combination of the specified ingredients in the
specified amounts.
[0126] Prodrugs and solvates of the compounds of the invention are
also contemplated herein. The term "prodrug", as employed herein,
denotes a compound that is a drug precursor which, upon
administration to a subject, undergoes chemical conversion by
metabolic or chemical processes to yield a compound of Formula I or
a salt and/or solvate thereof. A discussion of prodrugs is provided
in T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems
(1987) 14 of the A.C.S. Symposium Series, and in Bioreversible
Carriers in Drug Design, (1987) Edward B. Roche, ed., American
Pharmaceutical Association and Pergamon Press, both of which are
incorporated herein by reference thereto.
[0127] "Solvate" means a physical association of a compound of this
invention with one or more solvent molecules. This physical
association involves varying degrees of ionic and covalent bonding,
including hydrogen bonding. In certain instances the solvate will
be capable of isolation, for example when one or more solvent
molecules are incorporated in the crystal lattice of the
crystalline solid. "Solvate" encompasses both solution-phase and
isolatable solvates. Non-limiting examples of suitable solvates
include ethanolates, methanolates, and the like. "Hydrate" is a
solvate wherein the solvent molecule is H.sub.2O.
[0128] The compounds of Formula I can form salts which are also
within the scope of this invention. Reference to a compound of
Formula I herein is understood to include reference to salts
thereof, unless otherwise indicated. The term "salt(s)", as
employed herein, denotes acidic salts formed with inorganic and/or
organic acids, as well as basic salts formed with inorganic and/or
organic bases. In addition, when a compound of Formula I contains
both a basic moiety, such as, but not limited to a pyridine or
imidazole, and an acidic moiety, such as, but not limited to a
carboxylic acid, zwitterions ("inner salts") may be formed and are
included within the term "salt(s)" as used herein. Pharmaceutically
acceptable (i.e., non-toxic, physiologically acceptable) salts are
preferred, although other salts are also useful. Salts of the
compounds of the Formula I may be formed, for example, by reacting
a compound of Formula I with an amount of acid or base, such as an
equivalent amount, in a medium such as one in which the salt
precipitates or in an aqueous medium followed by
lyophilization.
[0129] Exemplary acid addition salts include acetates, ascorbates,
benzoates, benzenesulfonates, bisulfates, borates, butyrates,
citrates, camphorates, camphorsulfonates, fumarates,
hydrochlorides, hydrobromides, hydroiodides, lactates, maleates,
methanesulfonates, naphthalenesulfonates, nitrates, oxalates,
phosphates, propionates, salicylates, succinates, sulfates,
tartarates, thiocyanates, toluenesulfonates (also known as
tosylates,) and the like. Additionally, acids which are generally
considered suitable for the formation of pharmaceutically useful
salts from basic pharmaceutical compounds are discussed, for
example, by P. Stahl et al, Camille G. (eds.) Handbook of
Pharmaceutical Salts. Properties, Selection and Use. (2002) Zurich:
Wiley-VCH; S. Berge et al, Journal of Pharmaceutical Sciences
(1977) 66(1) 1-19; P. Gould, International J. of Pharmaceutics
(1986) 33 201-217; Anderson et al, The Practice of Medicinal
Chemistry (1996), Academic Press, New York; and in The Orange Book
(Food & Drug Administration, Washington, D.C. on their
website). These disclosures are incorporated herein by reference
thereto.
[0130] Exemplary basic salts include ammonium salts, alkali metal
salts such as sodium, lithium, and potassium salts, alkaline earth
metal salts such as calcium and magnesium salts, salts with organic
bases (for example, organic amines) such as dicyclohexylamines,
t-butyl amines, and salts with amino acids such as arginine, lysine
and the like. Basic nitrogen-containing groups may be quarternized
with agents such as lower alkyl halides (e.g. methyl, ethyl, and
butyl chlorides, bromides and iodides), dialkyl sulfates (e.g.
dimethyl, diethyl, and dibutyl sulfates), long chain halides (e.g.
decyl, lauryl, and stearyl chlorides, bromides and iodides),
aralkyl halides (e.g. benzyl and phenethyl bromides), and
others.
[0131] All such acid salts and base salts are intended to be
pharmaceutically acceptable salts within the scope of the invention
and all acid and base salts are considered equivalent to the free
forms of the corresponding compounds for purposes of the
invention.
[0132] Compounds of Formula I, and salts, solvates and prodrugs
thereof, may exist in their tautomeric form (for example, as an
amide or imino ether). All such tautomeric forms are contemplated
herein as part of the present invention.
[0133] All stereoisomers (for example, geometric isomers, optical
isomers and the like) of the present compounds (including those of
the salts, solvates and prodrugs of the compounds as well as the
salts and solvates of the prodrugs), such as those which may exist
due to asymmetric carbons on various substituents, including
enantiomeric forms (which may exist even in the absence of
asymmetric carbons), rotameric forms, atropisomers, and
diastereomeric forms, are contemplated within the scope of this
invention, as are positional isomers (such as, for example,
4-pyridyl and 3-pyridyl). Individual stereoisomers of the compounds
of the invention may, for example, be substantially free of other
isomers, or may be admixed, for example, as racemates or with all
other, or other selected, stereoisomers. The chiral centers of the
present invention can have the S or R configuration as defined by
the IUPAC 1974 Recommendations. The use of the terms "salt",
"solvate" "prodrug" and the like, is intended to equally apply to
the salt, solvate and prodrug of enantiomers, stereoisomers,
rotamers, tautomers, positional isomers, racemates or prodrugs of
the inventive compounds.
[0134] Compounds of Formula I can be highly selective, high
affinity Melanin Concentrating Hormone (MCH) receptor antagonists
useful for the treatment of obesity.
[0135] An aspect of this invention is a method of treating a mammal
(e.g., human) having a disease or condition mediated by MCH by
administering a therapeutically effective amount of at least one
compound of Formula I, or a pharmaceutically acceptable salt or
solvate of said compound to the mammal.
[0136] "Effective amount" or "therapeutically effective amount" is
meant to describe an amount of compound of the present invention
effective to treat a mammal (e.g., human) having a disease or
condition mediated by MCH, and thus producing the desired
therapeutic effect, for example weight loss, diabetes control.
[0137] A preferred dosage is about 0.001 to 1000 mg/kg of body
weight/day of the compound of Formula I or a pharmaceutically
acceptable salt or solvate thereof. An especially preferred dosage
is about 0.01 to 30 mg/kg of body weight/day of a compound of
Formula I, or a pharmaceutically acceptable salt or solvate of said
compound.
[0138] Still yet another aspect of this invention is a method of
treating obesity comprising administering to a mammal in need of
such treatment a therapeutically effective amount of at least one
compound of Formula I, or a pharmaceutically acceptable salt or
solvate of said compound.
[0139] A further aspect of this invention is a method for treating
eating and metabolic disorders such as bulimia and anorexia
comprising administering to a mammal a therapeutically effective
amount of at least one compound of Formula I, or a pharmaceutically
acceptable salt or solvate of said compound.
[0140] Another aspect of this invention is a method for treating
hyperlipidemia comprising administering to a mammal a
therapeutically effective amount of at least one compound of
Formula I or a pharmaceutically acceptable salt or solvate of said
compound.
[0141] Another aspect of this invention is a method for treating
cellulite and fat accumulation comprising administering to a mammal
a therapeutically effective amount of at least one compound of
Formula I, or a pharmaceutically acceptable salt or solvate of said
compound.
[0142] Another aspect of this invention is directed to a method for
treating type II diabetes comprising administering to a mammal a
therapeutically effective amount of at least one compound of
Formula I or a pharmaceutically acceptable salt or solvate of said
compound.
[0143] In addition to the "direct" effect of the compounds of this
invention on the MCH subtype, there are diseases and conditions
that can benefit from the weight loss such as, for example, insulin
resistance, impaired glucose tolerance, Type II Diabetes,
hypertension, hyperlipidemia, cardiovascular disease, gall stones,
certain cancers, and sleep apnea.
[0144] This invention is also directed to pharmaceutical
compositions, which comprise at least one compound of Formula I, or
a pharmaceutically acceptable salt or solvate of said compound and
at least one pharmaceutically acceptable carrier.
[0145] This invention is also directed to pharmaceutical
compositions for the treatment of obesity which comprise an obesity
treating amount of at least one compound of Formula I, or a
pharmaceutically acceptable salt or solvate of said compound and at
least one pharmaceutically acceptable carrier.
[0146] Still yet other aspects of this invention are combinations
of a compound of Formula I, or a pharmaceutically acceptable salt
or solvate of said compound and other compounds as described
below.
[0147] Accordingly, included within the invention is a method for
treating obesity comprising administering to a mammal (e.g., a
female or male human)
[0148] a. an amount of a first compound, said first compound being
a compound of Formula I, or a pharmaceutically acceptable salt or
solvate of said compound; and
[0149] b. an amount of a second compound, said second compound
being an antiobesity and/or anorectic agent such as a .beta..sub.3
agonist, a thyromimetic agent, an anoretic agent, or an NPY
antagonist and/or optionally a pharmaceutically carrier, vehicle or
diluent, wherein the amounts of the first and second compounds
result in a therapeutic effect (treating obesity).
[0150] Another aspect of this invention is a kit comprising:
[0151] a. an amount of a compound of Formula I, or a
pharmaceutically acceptable salt or solvate of said compound and a
pharmaceutically acceptable carrier, vehicle or diluent in a first
unit dosage form;
[0152] b. an amount of an antiobesity and/or anorectic agent such
as a .beta..sub.3 agonist, a thyromimetic agent, an anoretic agent,
or an NPY antagonist and a pharmaceutically acceptable carrier,
vehicle or diluent in a second unit dosage form; and
[0153] c. means for containing said first and second dosage forms
wherein the amounts of the first and second compounds result in a
therapeutic effect.
[0154] Preferred antiobesity and/or anorectic agents (taken singly
or in any combination thereof) in the above combination methods,
combination compositions and combination kits are:
[0155] phenylpropanolamine, ephedrine, pseudoephedrine,
phentermine, a cholecystokinin-A (hereinafter referred to as CCK-A)
agonist, a monoamine reuptake inhibitor (such as sibutramine), a
sympathomimetic agent, a serotonergic agent (such as
dexfenfluramine or fenfluramine), a dopamine agonist (such as
bromocriptine), a melanocyte-stimulating hormone receptor agonist
or mimetic, a melanocyte-stimulating hormone analog, a cannabinoid
receptor antagonist, a melanin concentrating hormone antagonist,
the OB protein (hereinafter referred to as "leptin"), a leptin
analog, a leptin receptor agonist, a galanin antagonist or a GI
lipase inhibitor or decreaser (such as orlistat). Other useful
anorectic agents include bombesin agonists, dehydroepiandrosterone
or analogs thereof, glucocorticoid receptor agonists and
antagonists, orexin receptor antagonists, urocortin binding protein
antagonists, agonists of the glucagon-like peptide-1 receptor such
as Exendin and ciliary neurotrophic factors such as Axokine.
[0156] Another aspect of this invention is a method of treating
diabetes comprising administering to a mammal (e.g., a female or
male human)
[0157] a. an amount of a first compound, said first compound being
a compound of Formula I, or a pharmaceutically acceptable salt or
solvate of said compound; and
[0158] b. an amount of a second compound, said second compound
being an aldose reductase inhibitor, a glycogen phosphorylase
inhibitor, a sorbitol dehydrogenase inhibitor, a protein tyrosine
phosphatase 1B inhibitor, a dipeptidyl protease inhibitor, insulin
(including orally bioavailable insulin preparations), an insulin
mimetic, metformin, acarbose, a PPAR-gamma ligand such as
troglitazone, rosaglitazone, pioglitazone or GW-1929, a
sulfonylurea, glipazide, glyburide, or chlorpropamide wherein the
amounts of the first and second compounds result in a therapeutic
effect.
[0159] This invention is also directed to a pharmaceutical
combination composition comprising: a therapeutically effective
amount of a composition comprising
[0160] a first compound, said first compound being a compound of
Formula I, or a pharmaceutically acceptable salt or solvate of said
compound;
[0161] a second compound, said second compound being an aldose
reductase inhibitor, a glycogen phosphorylase inhibitor, a sorbitol
dehydrogenase inhibitor, a protein tyrosine phosphatase 1B
inhibitor, a dipeptidyl protease inhibitor, insulin (including
orally bioavailable insulin preparations), an insulin mimetic,
metformin, acarbose, a PPAR-gamma ligand such as troglitazone,
rosaglitazone, pioglitazone, or GW-1929, a sulfonylurea, glipazide,
glyburide, or chlorpropamide; and optionally a pharmaceutical
carrier, vehicle or diluent.
[0162] Another aspect of this invention is a kit comprising:
[0163] a. an amount of a compound of Formula I, or a
pharmaceutically acceptable salt or solvate of said compound and a
pharmaceutically acceptable carrier, vehicle or diluent in a first
unit dosage form;
[0164] b. an amount of an aldose reductase inhibitor, a glycogen
phosphorylase inhibitor, a sorbitol dehydrogenase inhibitor, a
protein tyrosine phosphatase 1B inhibitor, a dipeptidyl protease
inhibitor, insulin (including orally bioavailable insulin
preparations), an insulin mimetic, metformin, acarbose, a
PPAR-gamma ligand such as troglitazone, rosaglitazone,
pioglitazone, or GW-1929, a sulfonylurea, glipazide, glyburide, or
chlorpropamide and a pharmaceutically acceptable carrier, vehicle
or diluent in a second unit dosage form; and
[0165] c. means for containing said first and second dosage forms
wherein the amounts of the first and second compounds result in a
therapeutic effect.
[0166] Preferably, the pharmaceutical preparation is in a unit
dosage form. In such form, the preparation is subdivided into
suitably sized unit doses containing appropriate quantities of the
active component, e.g., an effective amount to achieve the desired
purpose.
[0167] The quantity of active compound in a unit dose of
preparation may be varied or adjusted from about 1 mg to about 1000
mg, preferably from about 1 mg to about 50 mg, more preferably from
about 1 mg to about 25 mg, according to the particular
application.
[0168] The actual dosage employed may be varied depending upon the
requirements of the patient and the severity of the condition being
treated. Determination of the proper dosage regimen for a
particular situation is within the skill of the art. For
convenience, the total daily dosage may be divided and administered
in portions during the day as required.
[0169] The amount and frequency of administration of the compounds
of the invention and/or the pharmaceutically acceptable salts
thereof will be regulated according to the judgment of the
attending clinician considering such factors as age, condition and
size of the patient as well as severity of the symptoms being
treated. A typical recommended daily dosage regimen for oral
administration can range from about 1 mg/day to about 300 mg/day,
preferably 1 mg/day to 50 mg/day, in two to four divided doses.
[0170] For preparing pharmaceutical compositions from the compounds
described by this invention, inert, pharmaceutically acceptable
carriers can be either solid or liquid. Solid form preparations
include powders, tablets, dispersible granules, capsules, cachets
and suppositories. The powders and tablets may be comprised of from
about 5 to about 70 percent active ingredient. Suitable solid
carriers are known in the art, e.g. magnesium carbonate, magnesium
stearate, talc, sugar, lactose. Tablets, powders, cachets and
capsules can be used as solid dosage forms suitable for oral
administration.
[0171] For preparing suppositories, a low melting wax such as a
mixture of fatty acid glycerides or cocoa butter is first melted,
and the active ingredient is dispersed homogeneously therein as by
stirring. The molten homogeneous mixture is then poured into
convenient sized molds, allowed to cool and thereby solidify.
[0172] Liquid form preparations include solutions, suspensions and
emulsions. As an example may be mentioned water or water-propylene
glycol solutions for parenteral injection.
[0173] Liquid form preparations may also include solutions for
intranasal administration.
[0174] Aerosol preparations suitable for inhalation may include
solutions and solids in powder form, which may be in combination
with a pharmaceutically acceptable carrier, such as an inert
compressed gas.
[0175] Also included are solid form preparations which are intended
to be converted, shortly before use, to liquid form preparations
for either oral or parenteral administration. Such liquid forms
include solutions, suspensions and emulsions.
[0176] The compounds of the invention may also be deliverable
transdermally. The transdermal compositions can take the form of
creams, lotions, aerosols and/or emulsions and can be included in a
transdermal patch of the matrix or reservoir type as are
conventional in the art for this purpose.
[0177] Preferably the compound is administered orally.
[0178] Preferably, the pharmaceutical preparation is in unit dosage
form. In such form, the preparation is subdivided into unit doses
containing appropriate quantities of the active component, e.g., an
effective amount to achieve the desired purpose.
[0179] Compounds of Formula I can be produced by processes known to
those skilled in the art using either solution phase or solid phase
synthesis as shown in the following reaction schemes, in the
preparations and examples below.
Synthesis
[0180] The invention disclosed herein is exemplified by the
following preparations and examples which should not be construed
to limit the scope of the invention which is defined in the
appended claims. Alternative mechanistic pathways and analogous
structures will be apparent to those skilled in the art.
[0181] Where NMR data are presented, .sup.1H spectra were obtained
on either a Varian VXR-200 (200 MHz, .sup.1H), Varian Gemini-300
(300 MHz) or XL-400 (400 MHz) and are reported as ppm down field
from Me.sub.4Si with number of protons, multiplicities, and
coupling constants in Hertz indicated parenthetically. Where LC/MS
data are presented, analyses was performed using an Applied
Biosystems API-100 mass spectrometer and Shimadzu SCL-10A LC
column: Altech platinum C18, 3 micron, 33 mm.times.7 mm ID;
gradient flow: 0 min--10% CH.sub.3CN, 5 min--95% CH.sub.3CN, 7
min--95% CH.sub.3CN, 7.5 min--10% CH.sub.3CN, 9 min--stop. The
observed parent ion using electro spray ionization are given.
[0182] The following abbreviations are utilized throughout the
experimental procedures described below: [0183] OTf means
trifuoromethane sulfonate; [0184] TBDPSCI means
tert-butyldiphenylsilyl chloride; [0185] TBAF means
tetrabutylammonium fluoride; [0186] Ti(OiPr).sub.4 means titanium
isopropoxide; [0187] DPPA means diphenylphosphoryl azide; [0188]
DBU means 1,8 diazabicyclo[5.4.0]undec-7-ene; [0189] Ph.sub.3P
means triphenyl phosphine; [0190] Bn means benzyl; [0191] Me means
methyl; [0192] THF means tetrahydrofuran; [0193] DCM means
dichloromethane; [0194] Boc means Butoxycarbonyl; [0195] NMR means
nuclear magnetic resonance spectroscopy; [0196] MS means mass
spectrometry; [0197] room temperature or rt (ambient) means about
25.degree. C.
[0198] Alternative mechanistic pathways and analogous structures
within the scope of the invention would be apparent to those
skilled in the art.
EXPERIMENTAL EXAMPLES
[0199] The following examples illustrate the preparation of some of
the compounds of the invention and are not to be construed as
limiting the scope of the invention disclosed herein. ##STR26##
[0200] Aldehyde 3 (5.8 g, 51.3 mmol, 1 eq)/10 mL methanol was
treated with NaBH.sub.4 (2.1 g, 1.1 eq) at 0.degree. C. for 3 h.
The solvent was removed and EtOAc was added for extraction. Flash
chromatography (2:1 Hexane:EtOAc) provided 3.4 g of the desired
product (58% yield). .sup.1H NMR (CDCl.sub.3 .delta.): 4.90 (s, 2H)
7.27 (m, 1H) 7.70 (m, 1H) This material (3.4 g, 29.6 mmol, 1 eq)
was treated with TBDPSCI (8.94 g, 1.1 eq), imidazole (4.0 g, 2 eq)
in 20 mL DCM. The mixture was stirred for 14 h. After removal of
solvent, extraction with EtOAc and drying the organic layer with
Na.sub.2CO.sub.3, evaporation of the solvent afforded 10.5 g of the
desired product quantitavely. .sup.1H NMR (CDCl.sub.3 .delta.): 1.1
(s, 9H) 4.90 (s, 2H) 7.30-7.40 (m, 7H) 7.60-7.70 (m, 5H)
[0201] The thiazole (9.6 g, 27.1 mmol, 1 eq) was dissolved in 100
mL anhydrous THF at -78.degree. C. under nitrogen and treated with
18.6 mL nBuLi (1.6 M in hexane, 1.1 eq). After 5 min, 30 mL
trimethyltin chloride (1 M in THF, 1.1 eq) was added in. After 40
min, the reaction was quenched by brine solution. Removal of THF,
extraction with 5% EtOAc in hexane and flash chromatography (95:5
Hexane:EtOAc) provided 11.5 g of a mixture (starting
material:product 4=1:5, 73% yield). .sup.1H NMR (CDCl.sub.3
.delta.): 1.00 (s, 9H) 1.1 (s, 9H) 4.96 (s, 2H) 7.30-7.40 (m, 6H)
7.60-7.70 (m, 5H) For the Synthesis of [3,1,0]bicyclohexyl Analogs
(Method 1): ##STR27##
[0202] Compound 4 (10.53 g, 16.9 mmol, 1.2 eq) was mixed with
3-bromo-2-cyclopenten-1-ol 5 (2.3 g, 1 eq),
tetrakis(triphenylphosphine)palladium (1.63 g, 0.1 eq), LiCl (1.8
g, 3 eq), Na.sub.2CO.sub.3 (4.5 g, 3 eq) in 100 mL THF at
70.degree. C. under nitrogen for overnight. After removal of
solvent, extraction with EtOAc, flash chromatography (3:1 to 2:1
Hexane:EtOAc) provided 3.8 g of the desired product (62% yield).
.sup.1H NMR (CDCl.sub.3 .delta.): 1.10 (s, 9H) 1.80-1.95 (m, 2H)
2.40 (m, 1H) 2.60 (m, 1H) 2.80 (m, 1H) 4.86 (s, 2H) 4.90 (m, 1H)
6.00 (s, 1H) 7.30-7.40 (m, 6H) 7.44 (s, 1H) 7.60 (d, 4H, J=6.1 Hz)
HRMS for (MH.sup.+) C.sub.25H.sub.30NO.sub.2SSi: calcd: 436.1722;
found: 436.1767.
[0203] For the cyclopropanation reaction, 0.52 g samarium (Aldrich,
3.44 mmol, 5 eq) was flame dried under vacuum and cooled with
argon. Then it was treated with 4 mL anhydrous THF and cooled to
-50.degree. C. under argon. 0.28 mL diiodomethane (5 eq) was added
and the mixture was warmed up to -25.degree. C. when the color
turned dark green. The olefin (0.3 g, 1 eq) in 3 mL THF was
transferred into the green solution and the reaction was followed
by TLC. After one hour (temperature at 5.degree. C.), the TLC
showed disappearance of the olefin and the reaction was quenched by
saturated Na.sub.2CO.sub.3. Extraction with EtOAc three times.
Flash chromatography (2:1 Hexane:EtOAc) provided 0.16 g of the
desired product (52% yield). .sup.1H NMR (CDCl3 .delta. major
isomer): 0.80 (m, 1H) 1.00 (m, 1H) 1.10 (s, 9H) 1.30 (m, 1H) 1.60
(br s, 1H) 1.80 (m, 1H) 2.05-2.18 (m, 2H) 2.40 (m, 1H) 4.66 (br s,
1H) 4.82 (s, 2H) 7.30-7.40 (m, 7H) 7.60 (d, 4H, J=6.5 Hz)
[0204] The alcohol (1.14 g, 2.54 mmol, 1 eq) was treated with
Dess-Martin reagent (1.18 g, 1.1 eq) in 15 mL DCM for overnight.
The solvent was removed and extraction with 1:1 EtOAc and hexane
followed by washing with saturated Na.sub.2CO.sub.3. Flash
chromatography (2:1 Hexane:EtOAc) provided 1.08 g of the desired
product 6 (95% yield). .sup.1H NMR (CDCl.sub.3 .delta.): 1.05 (s,
9H) 1.20 (m, 1H) 1.66 (m, 1H) 2.10 (m, 1H) 2.20 (m, 2H) 2.30-2.50
(m, 2H) 4.85 (s, 2H) 7.30-7.40 (m, 7H) 7.60 (d, 4H, J=6.5 Hz) HRMS
for (MH.sup.+) C.sub.26H.sub.29NO.sub.2SSi: calcd: 447.1767; found:
447.1763.
[0205] Molecular sieve 3 .ANG. (3.8 g) was flame dried under
vacuum. After cooling, the ketone 6 (0.47 g, 1.06 mmol, 1 eq) was
mixed with N-(2-aminoethyl)pyrrolidine (0.14 g, 1.1 eq) and stirred
overnight. The mixture was treated with 0.071 g of NaBH.sub.4 and 5
mL of methanol. After 30 min, the mixture was filtered and flash
chromatography (8:1:92 MeOH:NH.sub.3:DCM) provided 0.57 g of the
desired product. .sup.1H NMR (CDCl.sub.3 .delta.): 0.90 (m, 1H)
1.05 (s, 9H) 1.15 (m, 1H) 1.60-1.90 (m, 4H) 2.00-2.15 (m, 5H) 2.70
(m, 2H) 2.90 (m, 2H) 3.02 (m, 1H) 3.10-3.25 (m, 3H) 3.58 (m, 1H)
4.80 (s, 2H) 7.34-7.40 (m, 7H) 7.60 (d, 4H, J=6.3 Hz) .sup.13C NMR
(CDCl.sub.3 .delta.): 14.7 19.7 23.9 26.3 27.2 28.7 32.3 32.5 47.6
54.6 56.5 60.2 64.5 128.3 130.4 133.1 135.9 137.9 144.8 170.1 HRMS
for (MH.sup.+) C.sub.32H.sub.44N.sub.3OSSi: calcd: 546.2774; found:
546.2778.
[0206] The amine intermediate was treated with 0.24 g of
4-fluoro-3-trifluoromethylphenyl isocyanate (1.2 eq) in 8 mL DCM.
After 2 h, 0.2 g of resin bound trisamine was added and after 1 h,
filtration through celite gave 0.64 g of the desired product 7. MS
for (MH.sup.+) C.sub.40H.sub.46F.sub.4N.sub.4O.sub.2SSi: 751.
##STR28##
[0207] The above urea, compound 7, (0.64 g) was treated with 1.2 mL
TBAF (1 M in THF) in 10 mL DCM for 3 h. After removal of solvent,
flash chromatography (5:1:95 MeOH:NH.sub.3:DCM) provided 0.33 g of
the desired alcohol (66% yield in three steps). .sup.1H NMR
(CDCl.sub.3 .delta.): 1.00 (m, 1H) 1.20 (m, 2H) 1.56 (m, 1H)
1.80-2.10 (m, 8H) 2.60-2.90 (m, 6H) 3.20-3.50 (m, 2H) 4.78 (s, 2H)
5.00 (m, 1H) 7.00 (m, 1H) 7.30 (s, 1H) 7.34-7.40 (m, 1H) 7.58 (m,
1H) 11.2 (s, 1H, N--H) .sup.13C NMR (CDCl.sub.3 .delta.): 15.9 23.7
24.2 30.2 31.4 42.8 53.9 55.1 59.7 62.3 117.4 117.6 124.4 137.7
138.2 144.6 154.6 155.4 158.1 170.0 HRMS for (MH.sup.+)
C.sub.24H.sub.29F.sub.4N.sub.4O.sub.2S: calcd: 513.1947; found:
513.1954.
[0208] The above product was treated with DBU (0.13 g, 1.3 eq),
DPPA (0.71 g, 4 eq) in 6 mL THF at 70.degree. C. for 2 h. After
removal of solvent, extraction with EtOAc and washing with
saturated NaHCO.sub.3, flash chromatography (5:1:95
MeOH:NH.sub.3:DCM) provided 0.29 g of the desired azide (84%
yield). .sup.1H NMR (CDCl.sub.3 .delta.): 1.01 (m, 1H) 1.20 (m, 2H)
1.60 (m, 1H) 1.80-2.10 (m, 8H) 2.60-2.70 (m, 6H) 2.82 (m, 1H)
3.30-3.50 (m, 2H) 4.50 (s, 2H) 5.01 (m, 1H) 7.00 (m, 1H) 7.40 (m,
2H) 7.58 (m, 1H) 11.1 (s, 1H, N--H) .sup.13C NMR (CDCl.sub.3
.delta.): 16.0 23.5 23.7 30.4 31.5 42.9 51.9 53.9 55.0 55.2 59.8
117.3 117.4 120.2 124.3 130.2 137.8 139.0 146.0 158.1 162.4 177.0
HRMS for (MH.sup.+) C.sub.24H.sub.27F.sub.4N.sub.7OS: calcd:
538.2012; found: 538.2019.
[0209] The above azide (96 mg, 0.18 mmol, 1 eq) was dissolved in 3
mL ethyl ether and 0.2 mL LiAlH.sub.4 (1 M in THF, 1.2 eq) was
added and heated to 38.degree. C. for 2 h. After removal of
solvent, extraction with EtOAc and washing with saturated
NaHCO.sub.3, preparative TLC (5:1:95 MeOH:NH.sub.3:DCM) provided 30
mg of the desired final product 1. .sup.1H NMR (CDCl.sub.3
.delta.): 1.00 (m, 1H) 1.20 (m, 2H) 1.50-1.75 (m, 5H) 1.80-1.95 (m,
4H) 2.08 (m, 2H) 2.60-2.80 (m, 4H) 2.90 (m, 1H) 3.20-3.50 (m, 2H)
4.00 (s, 2H) 5.00 (m, 1H) 7.00 (m, 1H) 7.30 (s, 1H) 7.38 (m, 1H)
7.58 (m, 1H) 11.2 (s, 1H, N--H) .sup.13C NMR (CDCl.sub.3 .delta.):
15.8 23.6 23.8 24.2 30.1 31.5 42.8 44.8 55.2 59.7 62.3 117.4 117.6
122.2 124.1 124.3 137.0 138.4 148.2 154.6 157.8 172.0 HRMS for
(MH.sup.+) C.sub.24H.sub.30F.sub.4N.sub.5O.sub.2S: calcd: 512.2107;
found: 512.2111. For the Synthesis of the Cross-Conjugated
Compound: ##STR29## Synthesis of [3,1,0]bicyclohexyl Analogs (Cross
Conjugated, Method 1)
[0210] Cyclopropanation reaction: To a solution of diethyl zinc (1
M solution in Hexanes, 1 mL, 5.5 eq.) in dichloroethane (10 mL) was
added chloroiodomethane (0.1 mL, 7.5 eq.) drop wise at 0.degree. C.
The solution was stirred at that temperature for 10 minutes. A
solution of olefin compound (0.1 g, 0.181 mmol) in dichloroethane
(5mL) was added drop wise at 0.degree. C. and stirred for 3 hours.
The reaction was quenched by the addition of NH.sub.4Cl solution
and extracted with ethyl acetate. The solvent was removed in vacuo
and the product was isolated by preparative TLC using 5% ethyl
acetate in hexane to afford 0.055 g (54%) of cyclopropanated
compound as oil. .sup.1H NMR (CDCl.sub.3 .delta.): 0.072 (s, 6H),
0.909 (s, 9H), 1.0-1.06 (m, 3H), 1.61-2.18 (m, 4H), 4.35 (m, 1H),
4.92 (s, 2H), 7.34 (s, 1H), 7.40 (m, 5H), 7.71 (m, 5H). MS for
(MH.sup.+) C.sub.32H.sub.46NO.sub.2SSi.sub.2.sup.+: calcd: 564.28;
found: 564.17 ##STR30## Data for Compound 14:
[0211] .sup.1H NMR (CDCl.sub.3d): 1.01 (s, 1H), 1.24 (m, 2H), 1.50
(s, 1H), 1.65-1.75 (m, 3H), 1.94 (m, 2H), 1.97-2.27 (m, 3H),
2.41-2.66 (m, 3H), 3.11-3.44 (m, 9H), 4.23 (m, 1H), 4.85 (s, 1H),
7.24 (m, 2H), 7.65 (m, 1H), 7.77 (m, 1H), 8.50 (br s, 1H). MS for
(MH.sup.+) C.sub.25H.sub.32F.sub.4N.sub.5O.sub.2S.sup.+: calcd:
542.22; found: 542.30. For the Synthesis of Cyclohexenyl Analogs
(Method 2): ##STR31## ##STR32##
[0212] Ketone 8 (9.9 g, 63.5 mmol, 1 eq)/200 mL
DCM/N-(2-aminoethyl)pyrrolidine (8.7 g, 1.2 eq)/Ti(OiPr).sub.4
(21.6 g, 1.2 eq) was stirred at room temperature for overnight. The
mixture was cooled to 0.degree. C. followed by addition of
NaBH.sub.4 (3.4 g, 1.4 eq). After another overnight stirring, 5 mL
of MeOH was added. After 2 h, saturated Na.sub.2CO.sub.3 was added
followed by extraction with EtOAc. Flash chromatography (10:1:90
MeOH:NH.sub.3:DCM) provided 9.8 g of the desired product (60%
yield). .sup.1H NMR (CDCl.sub.3 .delta.): 1.30-1.40 (m, 2H)
1.41-1.55 (m, 2H) 1.65 (br s, 6H) 1.80 (m, 2H) 2.40 (m, 5H) 2.52
(t, 3H, J=7.1 Hz) 2.62 (t, 3H, J=7.1 Hz) 3.80 (s, 4H) MS:
C.sub.14H.sub.27N.sub.2O.sub.2: 255 (MH).sup.+
[0213] This material (3.1 g, 12.2 mmol, 1 eq) was treated with
Boc.sub.2O (3.2 g, 1.2 eq), NaHCO.sub.3 (2 g, 1.5 eq) in 40 mL THF
and 40 mL water. The mixture was heated to 55.degree. C. for 48 h.
After cooling, extraction with EtOAc and drying the organic layer
with Na.sub.2CO.sub.3, evaporation of the solvent afforded
colorless syrup (4.4 g). This syrup was treated with
CeCl.sub.3.7H.sub.2O (9 g, 2 eq), NaI (0.54 g, 0.3 eq) in 80 mL of
CH.sub.3CN at 80.degree. C. under nitrogen for 2 h. Another 4.5 g
of CeCl.sub.3.7H.sub.2O (1 eq), NaI (0.54 g, 0.3 eq) and 60 mL of
CH.sub.3CN were added and the mixture was heated for 16 h. After
cooling to room temperature, extraction with EtOAc, drying with
Na.sub.2SO.sub.4, evaporation of solvent provided light yellow
syrup 9 and 9' (3.1 g total, 9:9'=1.4:1).
[0214] The above material (3.1 g, 10 mmol) was dissolved in 1:1
Toluene/THF 50 mL, cooled to -78.degree. C. followed by addition of
5.36 g of (Tf).sub.2NPh (15 mmol, 1.5 eq) and slow addition of
KHMDS solution 30 mL (0.5 N in Toluene, 1.5 eq). After 4 hours of
stirring, 40 mL of water was added into reaction mixture. This
reaction mixture was slowly warmed up to room temperature followed
by extraction of EtOAc. Flash chromatography (3:1:100
MeOH:NH.sub.3:DCM) gave the first fraction as colorless syrup 10
(1.5 g) 1H NMR (CDCl.sub.3 .delta.): 1.38 (s, 9H) 1.69 (m, 4H) 1.80
(m, 1H) 1.88 (m, 1H) 2.20 (m, 1H) 2.26-2.30 (m, 2H) 2.47 (m, 7H)
3.13 (br s, 2H) 4.03 (br s, 1H) 5.62 (m, 1H) Chromatography also
gave the second fraction as colorless syrup 10' (1.1 g) 1H NMR
(CDCl.sub.3 .delta.): 1.53 (m, 1H) 1.67 (m, 4H) 1.89-1.92 (m, 3H)
2.31 (m, 2H) 2.42 (m, 5H) 2.52 (t, 2H, J=6 Hz) 2.67 (m, 3H) 5.59
(m, 1H) ##STR33##
[0215] This material 10' (1 g, 2.9 mmol, 1 eq)/15 mL
DCM/4-fluro-3-chlorophenyl isocyanate (0.6 g, 3.5 mmol, 1.2 eq)
stirred at room temperature under N.sub.2 for 3 hours. Saturated
NaCl solution was added followed by extraction with EtOAc. Flash
chromatography (40:100 EtOAc/hexane) gave 11 as white solid (1.48
g, 96% yield). .sup.1H NMR (CDCl.sub.3 .delta.): 1.86 (m, 6H) 2.19
(m, 1H) 2.32-2.36 (m, 2H) 2.56 (m, 1H) 2.67-2.72 (m, 6H) 3.23 (m,
2H) 4.36 (m, 1H) 5.69 (m, 1H) 6.96 (t, 1H, J=8.8 Hz) 7.08 (m, 1H)
7.40 (m, 2H) 11.07 (m, 1H) ##STR34##
[0216] The conversion of 5 to 12 and then to 2 followed method 1 as
described above. Compound 2: .sup.1H NMR (CDCl.sub.3 .delta.):
1.60-1.95 (m, 9H) 2.19 (m, 1H) 2.32 (m, 1H) 2.56 (m, 2H) 2.60-2.80
(m, 6H) 3.20 (br s, 2H) 4.06 (br s, 1H) 4.40 (m, 1H) 5.90 (br s,
1H) 6.96 (t, 1H, J=8.8 Hz) 7.08 (m, 1H) 7.40 (m, 2H) 11.00 (br s,
1H) LC/MS: t=4.19 min. MS: C.sub.23H.sub.30ClFN.sub.5OS: 479
(MH).sup.+.
[0217] Further, by modifying the above schemes and experimental
examples, the following compounds can be prepared. ##STR35##
##STR36## Herg-Rb Two Phase Screen
[0218] Herg-Rb data (.mu.g/mL) (%) was determined by the following
two phase screen. The first phase is a cell-handling phase in which
cells are loaded with rubidium, drugs are added and efflux
initiated by KCl-depolarization. The second phase is measurement of
rubidium content in cell supernatants that are collected at the end
of the cell-handling phase. CHO cells expressing hERG in a stable
manner are used for these studies. Cells are plated into 96-well
dishes one day prior to study. After overnight culture, the normal
tissue culture medium is removed and cells are loaded with rubidium
for 3 hours in a HEPES-buffered physiological saline solution
containing 5 mM rubidium chloride in place of potassium chloride.
During the final 30 minutes of rubidium loading cells are
pre-equilibrated with test articles at 1.5 .mu.g/ml and 5 .mu.g/ml.
Cells are then washed with rubidium-free HEPES buffered
physiological saline solution containing 5 mM KCl to remove all
extracellular rubidium. The final step of the cell handling phase
is to depolarize the cells in HEPES buffered physiological saline
containing 50 mM KCl. This opens hERG channels and permits efflux
of rubidium. Supernatants are collected after 5 minutes and
rubidium content is measured using a flame atomic absorbance
spectrometer with a robot for sampling from 96-well plates
(ICR-8000, Aurora Biomed Inc., Vancouver, British Columbia). In
cases where the channel is blocked the amount of rubidium efflux is
reduced. Drug effects are calculated based on the difference
between wells with no added compound and wells in which there is
complete block of hERG channels with a well-known positive standard
(10 .mu.M dofetilide). TABLE-US-00001 MOL herg-Rb 5 herg-Rb 1.5 EX.
STRUCTURE .mu.g/mL (%) .mu.g/mL (%) 1 ##STR37## 26 22 2 ##STR38##
N/A N/A 3 ##STR39## 15 -1 4 ##STR40## 20 -1 5 ##STR41## 6 0 6
##STR42## N/A N/A 7 ##STR43## 10 -1 8 ##STR44## N/A N/A 9 ##STR45##
N/A N/A 10 ##STR46## 26 9 11 ##STR47## 14 9 12 ##STR48## 16 13 13
##STR49## 8 13 14 ##STR50## N/A N/A 15 ##STR51## -4 -4 16 ##STR52##
-8 -11 17 ##STR53## 14 0 18 ##STR54## -4 -5 19 ##STR55## 3 -10 20
##STR56## N/A N/A 21 ##STR57## N/A N/A
MCH Receptor Binding Assay:
[0219] Membranes from CHO cells expressing the MCH receptor were
prepared by lysing cells with 5 mM HEPES for 15 min at 4 C. Cell
lysates were centrifuged (12.5000.times.g, 15 min) and the pellet
was re-suspended in 5 mM HEPES. For each 96-well plate (Microlite,
Dynex Technologies), 1 mg of cell membranes were incubated with 10
mg of wheat germ agglutinin SPA beads (Amersham) for 5 min at 4 C
in a volume of 10 ml of binding buffer (25 mM HEPES, 10 mM
MGCl.sub.2, 10 mM NaCl, 5 mM MnCl.sub.2, 0.1% BSA). The
membrane/bead mixture was centrifuged (1500.times.g, 3.5 min), the
supernatant was aspirated, and the pellet was resuspended in 10 ml
binding buffer. The centrifugation, aspiration and resuspension
were then repeated. The membrane/bead mixture (100 .mu.l) was then
added to 96-well plates containing 50 .mu.l of 500 pM
[.sup.125I]-MCH (NEN) and 50 ml of the appropriate concentration of
compound (4.times. the desired final concentration). Nonspecific
binding was determined by including 1 .mu.M MCH in the binding
reaction. The binding reaction was incubated at room temperature
for 2 h. Plates were then analyzed in a TOPCOUNT microplate
scintillation counter (Packard). Data was analyzed and Ki values
were determined using GraphPad Prism.
[0220] Compounds with Ki values greater than 100 nM are designated
in the table below as C class compounds.
[0221] Compounds with Ki values between 30 and 100 nM are
designated in the table below as B class compounds.
[0222] Compounds with Ki values less than 30 nM are designated in
the table below as A class compounds.
[0223] In a preferred embodiment of the invention, Example 1, a Ki
value of 8 nM was observed.
[0224] While the present invention has been described in
conjunction with the specific embodiments set forth above, many
alternatives, modifications and other variations thereof will be
apparent to those of ordinary skill in the art. All such
alternatives, modifications and variations are intended to fall
within the spirit and scope of the present invention.
TABLE-US-00002 MOLECULAR EX. STRUCTURE Class 1 ##STR58## A 2
##STR59## C 3 ##STR60## C 4 ##STR61## C 5 ##STR62## B 6 ##STR63## A
7 ##STR64## A 8 ##STR65## C 9 ##STR66## C 10 ##STR67## A 11
##STR68## A 12 ##STR69## C 13 ##STR70## B 14 ##STR71## C 15
##STR72## B 16 ##STR73## A 17 ##STR74## B 18 ##STR75## A 19
##STR76## A 20 ##STR77## C 21 ##STR78## A
* * * * *